Injuries to the central nervous system (CNS) afflict millions of people in the United States each year and lack an effective therapy. A fundamental barrier to recovering lost function after such injuries is weak CNS regeneration. One of the most exciting discoveries in neurotherapeutics is that mammalian neurons can strongly regenerate their central axons into and beyond an injury site if a conditioning lesion is made on their peripheral sensory axons. Identifying critical components of the pathways involved in lesion conditioning would represent a key step toward successfully treating CNS injuries. The relative intractability of mammalian systems to genetic manipulation has hampered progress toward understanding lesion conditioning, but rapid breakthroughs could result from modeling lesion conditioning in a simpler, genetically-tractable organism. The small roundworm C. elegans is an extremely useful model organism with unparalleled genetic manipulability. In the late 1990s C. elegans researchers noted ectopic axons outgrowing from several neurons whose electrical activity was silenced by mutation. Using advanced laser surgery techniques to dissect individual neurons within intact adult C. elegans, we observe a strong lesion conditioning effect in these same sensory neurons. Recently-published data implicating suppression of electrical activity in mammalian lesion conditioning, as well as similarities between our regeneration experiments and previous studies on ectopic outgrowth in C. elegans, indicate that all these processes are highly related and share genetic pathways. The goal of the proposed research is to establish ectopic outgrowth in C. elegans as a genetically tractable model for mammalian lesion conditioning. Experiments for aim 1 will further demonstrate and characterize the reduction of neuronal activity that stimulates ectopic outgrowth and the lesion conditioning effect we observe in C. elegans. Results are expected to correlate reduced activity with axon regeneration and further ascertain the role of activity in ectopic outgrowth. Experiments for aim 2 seek to develop a forward screen to identify genes mediating ectopic axon outgrowth and lesion conditioned regeneration. The screen will identify novel genes that suppress both ectopic axon outgrowth and axon regeneration in C. elegans, with homologous mammalian genes mediating lesion conditioning in higher animals. By developing a genetically tractable model for lesion conditioning, these studies will lay the foundation for expedited and transformative research that has tremendous potential to illuminate critical components of this remarkable regeneration pathway. The knowledge gained will suggest new therapeutic avenues for treating CNS injuries by exploiting the nervous system's intrinsic regenerative capability.